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Adoptively Transferred T Cells Indirectly Regulate Murine Graft-Versus-Host Reactivity Following Donor Leukocyte Infusion Therapy in Mice¹

William R. Drobyski^2,*,, Sanja Vodanovic-Jankovic^*, and John Klein

Departments of ^* Medicine and Biostatistics and Bone Marrow Transplant Program, Medical College of Wisconsin, Milwaukee, WI 53226

The purpose of this study was to determine whether T cells were able to regulate graft-vs-host (GVH) reactivity mediated by ß T cells in murine recipients transplanted with MHC-mismatched marrow grafts. Studies were conducted using ex vivo-activated T cells because this was a more clinically relevant strategy, and these cells have been shown to be capable of facilitating alloengraftment without causing GVH disease (GVHD). Coadministration of activated T cells and naive ß T cells at the time of bone marrow transplantation (BMT) significantly exacerbated GVHD when compared with naive ß T cells alone. In contrast, when the administration of naive ß T cells was delayed for 2 wk post-BMT, survival was significantly enhanced in mice transplanted with BM plus activated T cells vs those given marrow cells alone. Mitigation of GVHD by activated T cells occurred only at high doses (150 x 10⁶) and was a unique property of T cells, as activated ß T cells were incapable of ameliorating the subsequent development of GVHD. Protection from GVHD was not due to the direct inhibition of naive ß T cells by T cells. Rather, T cells mediated this effect indirectly through donor BM-derived ß T cells that acted as the proximate regulatory population responsible for the decrease in GVH reactivity. Collectively, these data demonstrate that activated T cells are capable of modulating the ability of MHC-incompatible nontolerant ß T cells to cause GVHD after allogeneic BMT.

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